Racial and social-economic inequalities in systemic chemotherapy use among adult glioblastoma patients following surgery and radiotherapy

Not all patients with glioblastoma multiforme (GBM) eligible for systemic chemotherapy after upfront surgery and radiotherapy finally receive it. The information on patients with GBM was retrieved from the surveillance, epidemiology, and end results database. Patients who underwent upfront surgery or biopsy and external beam radiotherapy between 2010 and 2019 were eligible for systemic chemotherapy. The available patient and tumor characteristics were assessed using multivariable logistic regression and chi-squared test. Out of the 16,682 patients eligible, 92.1% underwent systemic chemotherapy. The characteristics linked to the lowest systemic chemotherapy utilization included tumors of the brain stem/cerebellum (P = 0.01), former years of diagnosis (P = 0.001), ≥ 80 years of age (P < 0.001), Hispanic, Non-Hispanic Asian, Pacific Islander, or Black race (P < 0.001), non-partnered status (P < 0.001), and low median household income (P = 0.006). Primary tumor site, year of diagnosis, age, race, partnered status, and median household income correlated with the omission of systemic chemotherapy in GBM in adult patients.


Data collection and selection
The definition of GBM was in accordance with the International Classification of Disease for Oncology; the diagnosis was made using the Adolescents and Young Adults Site Recode 2020 Revision, in which GBM is coded as 3.1.2.2 Glioblastoma-invasive.Pathological tumors were grouped into glioblastoma, NOS (9440/3); glioblastoma, isocitrate dehydrogenase mutant (IDH-mutant) (9445/3); glioblastoma, IDH-wildtype (9440/3); giant cell glioblastoma (9441/3) and gliosarcoma (9442/3).Based on the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO classification), IDH-wildtype glioblastoma includes giant cell glioblastoma and gliosarcoma 12 .Figure 1 provides a description of the inclusion and exclusion criteria.
Furthermore, only the patients who underwent cancer-directed surgery or biopsy and with positive histological or cytological diagnostic confirmation were included.Patients with only radiographical or clinical diagnostic confirmation were excluded.
Finally, only patients who underwent beam radiation after surgery were included.Patients with radioactive implants, radioisotopes, radiation methods, or sources not specified who refused radiation and never underwent radiation were excluded.
For the analysis of systemic chemotherapy, the database queries that returned patients with systemic chemotherapy after surgery or no systemic chemotherapy were included, while those with ambiguous information on post-surgery systemic chemotherapy were excluded from the database queries.
The socio-demographic information that was obtained for each patient consisted of their age, race/ethnicity, partnership status at the time of diagnosis, median household income of the county where they lived, and the rural or urban classification of the county of residence, which was determined by the US Department of Agriculture.

Statistical analysis
Statistical analyses were performed utilizing SPSS 26.0 software (IBM Corp, Armonk, NY).The characteristics of the patients were summarized and compared between those who received adjuvant systemic chemotherapy and those who did not, utilizing the chi-squared test at a significance level of 0.05 (Table 1).To estimate the odds ratios associated with various patient characteristics for receiving adjuvant systemic chemotherapy, a multivariable logistic regression analysis was conducted (Table 2).The multivariable analysis included the following variables: sex, year of diagnosis, age, race, primary site, laterality, 2016 WHO CNS Classification, partnered status, and median household incomes.

Ethical approval
The data within the SEER program are accessible to the public.This study adhered to the revised Declaration of Helsinki, and therefore, ethical consent was not deemed necessary.

Results
The final patient cohort for statistical analysis consisted of 16,682 individuals identified through the database query.Of these, 92.1% underwent adjuvant systemic chemotherapy, whereas 7.9% did not.The most common subsites were supratentorial GBMs situated in the frontal lobe (30.2%), temporal lobe (29%), parietal lobe (16.4%), and occipital lobe (4.4%).And 19.2% of the supratentorial GBMs were at other sites in the brain, including the overlapping lesions of the brain and brain, Not Otherwise Specified (NOS).The rare sites were the cerebellum (0.7%) and brain stem (0.1%).The common tumor pathologies were glioblastoma, NOS (77.2%), and glioblastoma, IDH-wildtype (22.2%).Glioblastoma, IDH-mutant (0.7%), was not a common subtype.Table 1 presents the summary of the demographic and tumor characteristics of individuals and their use of adjuvant systemic chemotherapy.Table 2 displays the odds ratios for each variable: sex, year of diagnosis, age, race, primary site, laterality, tumor pathology in 2016 WHO CNS Classification, partnered status, and household incomes.
Statistically significant differences in adjuvant systemic chemotherapy utilization were recorded in some of the independent variables.Patients with the primary tumor site cerebellum and brain stem had the lowest likelihood of undergoing systemic chemotherapy (83.2% and 87.5%, respectively) (Table 1).Patients with the primary tumor in all other sites, particularly in the occipital lobe (93%), frontal lobe (92.7%), temporal lobe (92.4%), parietal lobe (91.6%) and other sites in the brain (91.1%), were more likely to undergo systemic chemotherapy (Table 1).Patients with supratentorial GBM had approximately 2.3 times (OR: 2.34, 95%CI 1.45-3.77,P = 0.001) odds of undergoing systemic chemotherapy than cerebellar and brain stem, respectively (Table 2).There was no difference in adjuvant chemotherapy use among patients with variable tumor pathologies based on the 2016 WHO CNS Classification or with any laterality (Table 2).
Female individuals had a lower probability of undergoing adjuvant chemotherapy than male individuals (Table 1).Nevertheless, these differences were not statistically significant (Table 2).In terms of the year of diagnosis, the adjuvant chemotherapy uptake increased slightly with each year (OR 1.04, CI 1.02-1.07,P = 0.001) (Table 2).Systemic chemotherapy uptake decreased in general as age increased.Patients under 50 had the highest Vol:.( 1234567890 www.nature.com/scientificreports/rates of adjuvant chemotherapy utilization (96%), followed by those aged 50-59 (94.6%), respectively.These patients underwent systemic chemotherapy (Table 1).Moreover, 93.9% of patients aged 60-69 and 87.7% aged 70-79 underwent chemotherapy (Table 1).Patients in younger age groups had a greater likelihood of undergoing adjuvant chemotherapy than those aged 80 and above, and these differences reached the significance level (Table 2).Non-partnered individuals (divorced/separated/single/widowed) had approximately 33% lower odds of undergoing chemotherapy than those who were partnered (OR 0.67, CI 0.59-0.76,P < 0.001) (Table 2).Furthermore, significant differences in the odds of undergoing chemotherapy were noted on the basis of the median household income in individuals.The rates of adjuvant chemotherapy utilization increased slightly with increasing household income (OR 1.03, CI 1.01-1.06,P = 0.006) (Table 2).

Discussion
This research included individuals who had undergone surgery or biopsy and received post-surgery beam radiotherapy.The eligibility for adjuvant chemotherapy was determined on the basis of the available tumor and patient characteristics in the SEER database.However, around 7.9% of these individuals did not receive it.The findings of this research highlighted that primary tumor site, year of diagnosis, age, race, partnered status, and household income significantly correlate.In contrast, tumor pathology based on the 2016 WHO CNS Classification and laterality does not considerably correlate with the utilization of chemotherapy in GBM in adult patients (Table 2).

Tumor factors
The 2021 WHO Classification of Tumors of the CNS recognizes brainstem high-grade glioma as a diffuse midline glioma with H3 K27 alteration, typically affecting children and young adults 13 .Despite treatment with systemic therapy plus radiation, survival remains poor with a median of 10-11 months 14,15 , and systemic therapy(such as TMZ, other chemotherapy agents, or anti-EGFR antibody) may not improve outcomes but increase toxicity [16][17][18][19] .Therefore, based on the current results, the addition of systemic therapy is not actively recommended.Novel treatment modalities are needed to be investigated 20,21 .Cerebellar GBM, a rare brain cancer comprising just 0.24-1.00% of all GBM cases (0.24-1.00%) 22,23 exhibits distinct genomic characterization and biological behaviors that, unlike supratentorial GBM, are not yet fully understood 24,25 .Previous research based on the National Cancer Database has also revealed that cerebellar GBM were less likely to receive chemotherapy (57.4% vs. 64.3%,P value < 0.001) 26 .In this study, patients with supratentorial GBM were more likely to receive systemic chemotherapy compared to those with cerebellar or brainstem GBM(OR: 2.34, 95%CI 1.45-3.77,P = 0.001).These findings suggest that the treatment strategies for cerebellar GBM or brainstem GBM may be influenced by its unique biological properties, which could potentially affect the response to chemotherapy.New treatment strategies are needed to be investigated to provide greater therapeutic benefits for these patients.

Patient factors
The administration of adjuvant chemotherapy for GBM can result in adverse events such as hematologic toxicity, neutropenia, and fatigue, which may impact the quality of life of individuals.Therefore, it is crucial to consider these adverse effects against the risk of disease recurrence and the resulting significant morbidity 3 .Consequently, decisions regarding systemic chemotherapy are influenced by various factors, such as life expectancy, age, performance status, comorbidities, and the presence of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation [27][28][29] .The findings of this study indicate a tendency towards reduced chemotherapy utilization in elderly individuals, specifically in those over 80 years old.Patients under 50 have nearly ten times higher odds of receiving chemotherapy than those over 80 (OR 10.16, CL 7.85-13.16,P < 0.001).This is in line with literature that investigates the utilization of chemotherapy in elderly populations.The 2009 long-term 5-year follow-up subgroup analyses of the European Organisation for Research and Treatment of Cancer (EORTC) 26,981-National Cancer Institute of Canada (NCIC) CE.3 trial found that combination chemoradiation therapy conferred a survival advantage compared to radiotherapy alone.Nevertheless, this advantage was observed to decline with age, with individuals over 60 years of age experiencing less overall benefit than those receiving only RT (10.9 months vs. 11.8 months) 30,31 .Elderly populations with poor performance status might be unable to endure combined chemoradiation therapy.The 2012 Nordic trials found that hypofractionated RT (hRT) along with the omission of TMZ was superior to standard RT (sRT) for patients > 70 years of age (hRT vs. sRT HR: 0.59 (95% CI 0.37-0.93),P < 0.0001) 27 .For these patients, the omission of TMZ from hRT may be warranted.However, the 2017 Canadian Cancer Trials Group (CCTG)/EORTC 26,062 trial observed that combinatorial hRT and TMZ decreases the hazard ratio for death by 33% (HR: 0.67; 95% CI 0.56-0.80;P < 0.001) than hRT alone 32 and can be a viable option for elderly GBM with good performance status.Subgroup analyses also reported more survival advantage in patients with O6-methylguanine-DNA methyltransferase promoter methylation (mMGMT) treated with combinatorial hRT and TMZ compared with hRT alone (HR: 0.53; 95% CI 0.38-0.73;P < 0.001).Based on the evidence from these prospective studies, the treatment regimen needs to be tailored with the consideration of performance status and the presence of mMGMT for elderly GBM.Unfortunately, the SEER database does not currently provide information on individual performance status or MGMT status.
Numerous studies have well-documented the influence of partnered status on treatment patterns and outcomes [33][34][35][36][37][38] .A previous study found that married patients with GBM had a median overall survival advantage www.nature.com/scientificreports/(married vs. unmarried: 10 vs. 7 months, P < 0.001).However, fundamental mechanisms responsible for this impact are not yet entirely comprehended 39 .This may be attributed to the provision of economic and mental support from partners, which enables the patients to receive an improved quality of treatment.This research confirmed that unpartnered individuals had a lower probability of undergoing adjuvant systemic chemotherapy than partnered individuals (OR 0.67, CI 0.59-0.76,P < 0.001).The findings of the study provide additional evidence to support the significant influence of partner support on receiving definitive treatment, such as adjuvant chemotherapy, which may be due to the particularly arduous nature of the treatment.Thus, providing additional support resources for non-partnered individuals may aid in narrowing this disparity.The role of race as a significant factor contributing to disparities in cancer treatment patterns and outcomes has been extensively studied.Black non-Hispanics and Hispanics had a lower probability of undergoing radiotherapy and chemotherapy than non-Hispanic white patients 40 .Taking into account these well-established disparities, it is not surprising that this analysis determined trends indicating that Black, Hispanic, Non-Hispanic Asian, or Pacific Islander individuals had a lower probability of undergoing systemic chemotherapy than other individuals.
Previous research indicates that the addition of TMZ to GBM treatment raises the average cost from $35,017(surgery + XRT) to $82,018(surgery + XRT + TMZ) , highlighting the need for financial support 41 .In our research, an increase in household income was associated with a statistically significant rise in the likelihood of receiving systemic chemotherapy, underscoring the influence of economic support on treatment pattern decisions.The observed disparities in systemic chemotherapy use likely stem from the U.S. insurance-based healthcare system.The significant variables related to the wealth of the patient/household underscore the role of economic factors in accessing and receiving treatment patterns.It is plausible that insurance coverage, out-ofpocket costs, and the financial burden on patients and their families can significantly affect the decision-making process regarding chemotherapy treatment.This study also found that adjuvant systemic chemotherapy uptake grows slightly year by year 11 .This is concomitant with the report from a single academic institution in Lyon, France, that showed that patients received TMZ more frequently in 2008 than in 2004 (71% vs. 39%, P < 0.05).It is understandable that introducing a new treatment approach and gaining patient acceptance may require time.
There were no significant differences in receiving adjuvant systemic chemotherapy based on tumor laterality or pathology by the 2016 WHO CNS Classification.The 2021 WHO CNS Classification recently stratified most IDH-mutant GBM into astrocytoma, WHO grade 4 13 .Numerous studies have shown that the presence of IDH1 mutation serves as a predictive biomarker for TMZ sensitivity in low-grade gliomas and secondary GBM 42,43 .However, the complete IDH status details of 77.2% of the population were unknown.

Limitations
Due to the nature of the population-based analysis, access to all factors involved in clinical decision-making, such as detailed radiology or pathology reports that indicate tumor size and extent of resection, was unavailable.The SEER database did not contain information on critical factors such as performance status and MGMT status in GBM, which could affect treatment decisions.We hope that future research endeavors prioritize the integration of comprehensive molecular data, such as MGMT status, into analyses.Patient comorbidities and risk factors were not available to us.Specific systemic chemotherapy drugs or the dose or cycles were unavailable to us.In addition, the use of hRT or concurrent chemotherapy was not within the scope of this study and may warrant further investigation in the future.
Although there are limitations to the SEER database, it remains a valuable resource for examining treatment patterns at the population level and generating hypotheses and opportunities for further investigation.This research successfully identified various factors that are significantly associated with the use of systemic adjuvant chemotherapy among GBM individuals.

Conclusion
In conclusion, it was found that roughly 7.9% of individuals with GBM in adult patients do not undergo adjuvant chemotherapy after surgery as recommended by current evidence-based guidelines.Patients with certain subsite cancers, such as brain stem/cerebellar tumors, as well as those diagnosed in earlier years, aged ≥ 80, of Hispanic, Non-Hispanic Asian, Pacific Islander, or Black race, non-partnered, and with lower median household income, are less likely to undergo adjuvant chemotherapy.Laterality or tumor pathology is not significantly correlated with adjuvant chemotherapy uptake.Furthermore, it was found that all treatment decisions are tailored to the individual patient, and crucial patient-specific data are not assessable at the population level.Additional research is warranted to determine which kind of GBM in adult patients properly omits adjuvant chemotherapy after surgery and adjuvant RT.

Figure 1 .
Figure 1.Flow chart indicating the inclusion and exclusion criteria of this study.

Table 1 .
Frequency of adjuvant systemic chemotherapy utilization based on age, race/origin, partnered status, median household income, and rural-urban classification.

Table 2 .
Multivariate analysis showing association of likelihood of undergoing systemic chemotherapy.